In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short term help maintaining sleep, on the basis of weak evidence.[13][14] The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar.[13] A 2015 AHRQ review of treatments for insomnia had similar findings.[15]

A 2010 review found that topical doxepin is useful to treat itchiness.[16]

A 2010 review of treatments for chronic hives found that doxepin had been superseded by better drugs but was still sometimes useful as a second line treatment.[17]

Its use in pregnant and lactating women is advised against, although the available preclinical (based on animal studies) evidence suggests it is unlikely to cause any deleterious effects on fetal development,[7] the lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus[7] and it is known to cross the placenta.[7] Doxepin is secreted in breast milk[1] and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.[20]

Like other TCAs, doxepin is highly toxic in cases of overdose.[22] Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose.[7] Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin.[7] Supportive measures to prevent respiratory aspiration is also advisable.[7] Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose.[7] Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects.[7]Haemodialysis is not recommended due to the high degree of protein binding with doxepin.[7] ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.[7]

Based on its IC50 values for monoamine reuptake inhibition, doxepin is relatively selective for inhibition of norepinephrine reuptake with much weaker effects on serotonin reuptake and negligible influence on dopamine reuptake.[24][25]

The major metabolite of doxepin, nordoxepin (desmethyldoxepin), is pharmacologically active similarly,[4] but relative to doxepin, is much more selective as a norepinephrine reuptake inhibitor.[40][41] In general, the demethylated variants of tertiary amine TCAs like doxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.[40][41][42]

Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day.[43][44] Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg,[45][44] although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia.[46] At low doses, below 25 mg, doxepin is a pure antihistamine.[43] At antidepressant doses of above 25 mg, doxepin has significant antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.[45][43][44]

Doxepin is a mixture of (E) and (Z)stereoisomers with an approximate ratio of 85:15.[5] When doxepin was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio.[5] (Z)-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than (E)-doxepin.[5] The selectivity of doxepin for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of (E)-doxepin in the mixture.[5] Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-Z isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake.[5][24]

Doxepin is a highly potent antihistamine, with this being its strongest activity.[39][43][48][4] In fact, doxepin has been said to be the most or one of the most potent H1 receptor antagonists available, with one study finding an in vitro Ki of 0.17 nM.[26] It is the most potent and selective H1 receptor antagonist of the TCAs (although the tetracyclic antidepressant (TeCA) mirtazapine is slightly more potent),[45][49][50] and other sedating antihistamines, for instance the over-the-counterdiphenhydramine (Ki = 16 nM) and doxylamine (Ki = 42 nM), show far lower affinities for this receptor in comparison.[4] The affinity of doxepin for the H1 receptor is far greater than its affinity for other sites,[4] and 10- to 100-fold higher doses are needed for antidepressant effects.[51][48] In accordance, although it is often described as a "dirty drug" due to its highly promiscuous binding profile,[48] doxepin acts as a highly selective antagonist of the H1 receptor at very low doses (less than 10 mg; typically 3 to 6 mg).[43][4][44] At these doses, it notably has no clinically relevant anticholinergic effects such as dry mouth or cognitive/memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.[43][4][44]

The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses.[4][48] The incidence of side effects with doxepin and its safety at these doses was similar to that of placebo in clinical trials; the most frequent side effects were headache and somnolence/sedation, both with an incidence of less than 5%.[43][4] Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed.[48] Clinical evidence of H1 receptor antagonists and TCAs for the treatment insomnia shows mixed effectiveness and is limited in its quality due to weaknesses like small sample sizes and poor generalizability.[44][52] However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent tolerability and safety.[44][52] Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.[52][53]

The effect sizes of very-low-dose doxepin in the treatment of insomnia range from small to medium,[44] these include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency.[44] Conversely, very-low-dose doxepin shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure,[44] this is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency.[44] However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset.[44] A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults.[44] However, the incidence of adverse effects appeared to increase with longer treatment duration.[44] A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep.[44] This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.[44]

At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia.[4] Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration.[52] This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness.[52] It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week).[52] It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H1 receptor of the latter or may have to do with the use of optimal doses.[48] Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion.[52] This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65.[52] Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade.[25]

Antagonism of the H1, 5-HT2A, 5-HT2C, and α1-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin.[54][55][56] Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses.[54] However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug.[44] In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks).[44] Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed,[44] at these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question.[44] In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.[48]

Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease cortisol levels by 16% in adults with chronic insomnia and to increase melatonin production by 26% in healthy volunteers.[4] In individuals with neuroendocrine dysregulation in the form of nocturnal melatonin deficiency presumably due to chronic insomnia, very-low-dose doxepin was found to restore melatonin levels to near-normal values after 3 weeks of treatment.[38] These findings suggest that normalization of the hypothalamic–pituitary–adrenal axis and the circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.[4][38]

Doxepin has been identified as an inhibitor of CYP2D6in vivo in a study of human patients being treated with 75 to 250 mg/day for depression.[57] While it significantly altered metabolic ratios for sparteine and its metabolites, doxepin did not convert any of the patients to a different metabolizer phenotype (e.g., extensive to intermediate or poor).[57] Nonetheless, inhibition of CYP2D6 by doxepin could be of clinical importance.[57]

Doxepin is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver,[4] resulting in a mean oralbioavailability of approximately 29%.[6] Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food.[4] Plasma concentrations of doxepin with antidepressant doses are far greater, ranging between 50 and 250 ng/mL (180 to 900 nmol/L).[58]Area-under-curve levels of the drug are increased significantly when it is taken with food.[4]

Nordoxepin is a mixture of (E) and (Z)stereoisomers similarly to doxepin.[5] Whereas pharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of (E)- and (Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the (E)- and (Z)-stereoisomers of nordoxepin, due to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.[5]

Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.

Individuals can be categorized into different types of cytochrome P450 metabolizers depending on which genetic variations they carry, these metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.

A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes.[60] In CYP2D6 extensive, intermediate, and poor metabolizers, the mean clearance rates of (E)-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor).[60] In addition, the bioavailability of (E)-doxepin was about 2-fold lower in extensive relative to poor CYP2D6 metabolizers, indicating a significant role of CYP2D6 in the first-pass metabolism of (E)-doxepin.[60] The clearance of (E)-doxepin in CYP2C9 slow metabolizers was also significantly reduced at 238 L/hour.[60] CYP2C19 was involved in the metabolism of (Z)-doxepin, with clearance rates of 191 L/hour in CYP2C19 extensive metabolizers and 73 L/hour in poor metabolizers (~2.5-fold difference).[60]Area-under-the-curve (0–48 hour) levels of nordoxepin were dependent on the genotype of CYP2D6 with median values of 1.28, 1.35, and 5.28 nM•L/hour in CYP2D6 extensive, intermediate, and poor metabolizers, respectively (~4-fold difference between extensive and poor).[60] Taken together, doxepin metabolism appears to be highly stereoselective, and CYP2D6 genotype has a major influence on the pharmacokinetics of (E)-doxepin.[60] Moreover, CYP2D6 poor metabolizers, as well as patients taking potent CYP2D6 inhibitors (which can potentially convert a CYP2D6 extensive metabolizer into a poor metabolizer), may be at an increased risk for adverse effects of doxepin due to their slower clearance of the drug.[60]

Another study assessed doxepin and nordoxepin metabolism in CYP2D6 ultra-rapid, extensive, and poor metabolizers following a single 75 mg oral dose.[62] They found up to more than 10-fold variation in total exposure to doxepin and nordoxepin between the different groups,[62] the researchers suggested that in order to achieve equivalent exposure, based on an average dose of 100%, the dosage of doxepin might be adjusted to 250% in ultra-rapid metabolizers, 150% in extensive metabolizers, 50% in intermediate metabolizers, and 30% in poor metabolizers.[62]

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969,[38] it was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.[44][69]

The oral formulations of doxepin are FDA-approved for the treatment of depression and sleep-maintenance insomnia and its topical formulations are FDA-approved the short-term management for some itchy skin conditions.[71] Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.[20][72]

^ abcRoth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.

1.
Dosulepin
–
It is not used in the United States. Dosulepin is used for the treatment of major depressive disorder and neuropathic pain, dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder. There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants. Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin, sympathomimetics may potentiate the sympathomimetic effects of dosulepin. Dosulepin may have its postural hypotensive effects potentiated by diuretics, anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold. The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants, dosulepin may be particularly toxic in overdose compared to other TCAs. The onset of effects is around 4–6 hours after dosulepin is ingested. In order to minimise the risk of overdose it is advised that only receive a limited number of tablets at a time so as to limit their risk of overdosing. It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses, the medication should also be kept out of reach of children. Dothiepin is readily absorbed from the intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite. Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration and it is distributed in breast milk and crosses the placenta and blood-brain barrier. It is highly bound to proteins, and has a whole-body elimination half-life of 51 hours

2.
Drug nomenclature
–
Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. Generic names for drugs are nowadays constructed out of affixes and stems that classify the drugs into different categories, a marketed drug might also have a company code or compound code. The chemical names are the names, based on the molecular structure of the drug. There are various systems of nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name, chemical names are typically very long and too complex to be commonly used in referring to a drug. Sometimes, a company that is developing a drug might give the drug a company code, for example, CDP870 is UCB’s company code for Cimzia. Many of these codes, although not all, have prefixes that correspond to the company name, during development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, and it will apply for a generic name for that country. It will also apply for an International Nonproprietary Name through the World Health Organization, nowadays the national nonproprietary names are usually the same as the INN. The generic names usually indicate via their stems what drug class the drug belongs to, for example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix. Otherwise the 2 names are both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole, similarly, co-codamol is codeine-acetaminophen, and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar co-prefixed BANs are still current, for drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name. The term trade name is a term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizers trade name for atorvastatin, a cholesterol-lowering medication, Drug names are often subject to legal regulation, including approval for new drugs and on packaging to establish clear rules about adulterants and fraudulent or misleading labelling. A national formulary is often designated to define drug names for regulatory purposes, unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant. This pattern is important for the literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug and they will often state which brand was used, for methodologic validity, but they do so in a way that makes clear the absence of endorsement. For example, the 2015 American Society of Hematology publication policies say, Non-proprietary names should be used and he first letter of the name of a proprietary drug should be capitalized

3.
Drugs.com
–
Drugs. com is an online pharmaceutical encyclopedia which provides drug information for consumers and healthcare professionals primarily in the USA. The domain Drugs. com was registered by Bonnie Neubeck in 1994. In 1999 at the height of the boom, Eric MacIver purchased an option to buy the domain from Neubeck. com. Venture Frogs sold the drugs. com domain name to an investor in June 2001. The Drugs. com website is owned and operated by the Drugsite Trust, the Drugsite Trust is a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton The Drugs. com website was officially launched in September 2001. Stedmans, AHFS, Harvard Health Publications, Mayoclinic, North American Compendiums, in March 2008, Drugs. com announced the release of Mednotes —an online personal medication record application which connected to Google Health. In May 2010, U. S. FDA announced a collaboration with Drugs. com to distribute consumer health updates on the Drugs. com website, Drugs. com is certified by the TRUSTe online privacy certification program and the HONcode Health on the Net Foundation

4.
Regulation of therapeutic goods
–
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc

5.
Food and Drug Administration
–
The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. As of 2017, 3/4th of the FDA budget is funded by the pharmaceutical companies due to the Prescription drug user fee act and these include regulating lasers, cellular phones, condoms and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice, the Commissioner reports to the Secretary of Health and Human Services. Dr. Robert M. Califf, MD is the current commissioner, who took over in February 2016 for Dr. Stephen Ostroff, the FDA has its headquarters in unincorporated White Oak, Maryland. The agency also has 223 field offices and 13 laboratories located throughout the 50 states, the United States Virgin Islands, in 2008, the FDA began to post employees to foreign countries, including China, India, Costa Rica, Chile, Belgium, and the United Kingdom. The site was renamed from the White Oak Naval Surface Warfare Center to the Federal Research Center at White Oak, the first building, the Life Sciences Laboratory, was dedicated and opened with 104 employees on the campus in December 2003. Only one original building from the facility was kept. All other buildings are new construction, the project is slated to be completed by 2017, assuming future Congressional funding While most of the Centers are located in the Washington, D. C. The Office of Regulatory Affairs is considered the eyes and ears of the agency, the Office of Regulatory Affairs is divided into five regions, which are further divided into 20 districts. Districts are based roughly on the divisions of the federal court system. Each district comprises a main office and a number of Resident Posts. ORA also includes the Agencys network of laboratories, which analyze any physical samples taken. Though samples are usually food-related, some laboratories are equipped to analyze drugs, cosmetics, the Office of Criminal Investigations was established in 1991 to investigate criminal cases. Unlike ORA Investigators, OCI Special Agents are armed, and dont focus on aspects of the regulated industries. In many cases, OCI pursues cases involving Title 18 violations, OCI Special Agents often come from other criminal investigations backgrounds, and work closely with the Federal Bureau of Investigation, Assistant Attorney General, and even Interpol. OCI receives cases from a variety of sources—including ORA, local agencies, OCI is a smaller branch, comprising about 200 agents nationwide. The FDA frequently works with federal agencies, including the Department of Agriculture, Drug Enforcement Administration, Customs and Border Protection. Often local and state government agencies also work with the FDA to provide regulatory inspections, the FDA regulates more than US$1 trillion worth of consumer goods, about 25% of consumer expenditures in the United States

6.
Topical medication
–
A topical medication is a medication that is applied to a particular place on or in the body, as opposed to systemically. Most often this means application to surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions. Many topical medications are epicutaneous, meaning that they are applied directly to the skin, as a route of administration, the topical route is contrasted with the enteral route, the intravenous route, and others. A topical effect, in the sense, may refer to a local, rather than systemic. However, many topically administered drugs have effects, because they reach the circulation after being absorbed by the tissues. Topical medications differ from other types of drugs because mishandling them can lead to certain complications in a patient or administrator of the drug. Some hydrophobic chemicals, such as hormones, can be absorbed into the body after being applied to the skin in the form of a cream, gel. Transdermal patches have become a means of administering some drugs for birth control, hormone replacement therapy. One example of an antibiotic that may be applied topically is chloramphenicol, a medications potency often is changed with its base. For example, some topical steroids will be classified one or two strengths higher when moving from cream to ointment, as a rule of thumb, an ointment base is more occlusive and will drive the medication into the skin more rapidly than a solution or cream base. The manufacturer of each product has total control over the content of the base of a medication. Although containing the active ingredients, one manufacturers cream might be more acidic than the next. For example, a formulation of miconazole antifungal cream might irritate the skin less than an athlete foot formulation of miconazole cream. These variations can, on occasion, result in different clinical outcomes, no comparative potency labeling exists to ensure equal efficacy between brands of topical steroids. Studies have confirmed that the potency of some topical steroid products may differ according to manufacturer or brand, however, in a simple base like an ointment, much less variation between manufacturers is common. In dermatology, the base of a medication is often as important as the medication itself. It is extremely important to receive a medication in the correct base, a pharmacist should not substitute an ointment for a cream, or vice versa, as the potency of the medication can change. As a result, what the manufacturers marketing department chooses to list on the label of a medication might be completely different from what the form would normally be called

7.
Intravenous administration
–
Intravenous therapy is the infusion of liquid substances directly into a vein. Intravenous infusions are commonly referred to as drips, the intravenous route is the fastest way to deliver fluids and medications throughout the body. Intravenous therapy may be used for administration, to correct electrolyte imbalances, to deliver medications. IVs can be categorized by type of vein the tube inserted, called the catheter. A peripheral IV is used on peripheral veins and this is the most common type of IV therapy used. Central IV lines have their catheters that are advanced through a vein and empty into a central vein, usually the superior vena cava. Other advantages are that because it empties near the heart, medications can also be distributed to the rest of the body. As there is room for multiple parallel compartments within the catheter, caregivers can also measure central venous pressure and other physiological variables through the line. They are also longer, which as reflected in Poiseuilles law, requires higher pressure to achieve the same flow, central IV lines carry risks of bleeding, infection, gangrene, thromboembolism and gas embolism. Surrounding structures such as the pleura and carotid artery are also at risk of damage with the potential for pneumothorax or even cannulation of the artery. There are several types of central IVs, depending on the route that the catheter takes from the outside of the body to the vein, typical uses for a PICC include, long chemotherapy regimens, extended antibiotic therapy, or total parenteral nutrition. This is usually done by measuring the distance to a landmark, such as the suprasternal notch. An X-ray must be used to verify that the tip is in the place when fluoroscopy was not used during the insertion. A PICC may have a tube and connector, two or three compartments, each with its own external connector. Power-injectable PICCs are now available as well, from the outside, a single-lumen PICC resembles a peripheral IV, except that the tubing is slightly wider. The insertion site requires better protection than that of a peripheral IV, however, a PICC poses less of a systemic infection risk than other central IVs, because the insertion site is usually cooler and dryer than the sites typically used for other central lines. This helps to slow the growth of bacteria which could reach the bloodstream by traveling under the skin along the outside of the catheter, although special training is required, a PICC does not require the skill level of a physician or surgeon. It is also externally unobtrusive, and with proper hygiene and care can be left in place for months to years if needed for patients who require extended treatment, also, as a PICC travels through the axilla, it can become kinked, causing poor function

8.
Intramuscular injection
–
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of alternative methods for the administration of medications. Muscles have larger and more vessels than subcutaneous tissue and injections here usually have faster rates of absorption than subcutaneous injections or intradermal injections. Depending on the site, an administration is limited to between 2 and 5 milliliters of fluid. Platelet-rich plasma injections can be administered intramuscularly, certain substances are injected intramuscularly for recreational purposes. Possible sites for IM injection include, deltoid, dorsogluteal, rectus femoris, vastus lateralis, sites that are bruised, tender, red, swollen, inflamed or scarred are avoided. The deltoid muscle site is recommended for use with injections of small volume, usually equal or less than 1 ml and this site is not recommended for repeated injections, due to its small area, it is difficult to rotate the injection site. To locate the site, palpate the lower edge of the acromion process, inject in the upside down triangle that forms with its base at the acromion process and its midpoint in line with the axilla. The ventrogluteal site is recommended for injections requiring a larger volume to be administered, greater than 1 ml and it is also given for narcotic, antibiotic, sedative and anti-emetic medications. To locate the site, place the palm of your hand over the greater trochanter. The right hand is used for the hip and left hand is used for the right hip. Place the index finger on the superior iliac spine and run the middle finger back along the iliac crest. The injection is given in the center of the triangle that is formed, the vastus lateralis site is the recommended site for infants less than 7 months old and those unable to walk, with loss of muscular tone. To locate the site, divide the front thigh into thirds vertically and horizontally to make nine squares and inject in the outer middle square. Use of this site is associated with skin and tissue trauma, muscle fibrosis and contracture, haematoma, nerve palsy and paralysis, as well as infectious processes such as abscess and gangrene. The injection site is located by dividing the buttock into four with a plus shaped cross, the selected site is cleansed with an antimicrobial and is allowed to dry. It is injected with the dominant hand using a quick, darting motion perpendicular to the body at an angle between 72 and 90 degrees, as a faster injection is less painful. The needle is then stabilized with the nondominant hand while the dominant hand slides to the plunger to slowly instill the medication, the CDC does not recommend the outdated practice of aspirating for blood to rule out injecting into a blood vessel

9.
Prescription drug
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A prescription drug is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription, the reason for this difference in substance control is the potential scope of misuse, from drug abuse to practicing medicine without a license and without sufficient education. Different jurisdictions have different definitions of what constitutes a prescription drug, rx is often used as a short form for prescription drug in North America- a contraction of the Latin word recipe meaning take. Prescription drugs are often dispensed together with a monograph that gives detailed information about the drug, the use of prescription drugs has been increasing since the 1960s. In the U. S. 88% of older adults use at least 1 prescription drug, who is able to prescribe the drug. When purchasing a drug under the PBS the maximum price a consumer pays is the patient co-payment contribution and those covered by government entitlements and those covered under the Repatriation Pharmaceutical Benefits Scheme have a reduced co-payment, which is $6.00 in 2014. The table below indicates the changes in co-payments over the years and these co-payments are compulsory and cannot be discounted by pharmacies under any circumstances. Private prescriptions are issued for medicines not covered on the PBS, or being used off-label, the patient pays the pharmacy for medicines privately prescribed. In the United Kingdom the Medicines Act 1968 and Prescription Only Medicines Order 1997 contain regulations that cover the supply of sale, use, prescribing is also covered by this legislation. A patient visits a medical practitioner or dentist authorised to prescribe drugs and certain other medical items, also, suitably qualified and experienced nurses and pharmacists may be independent prescribers. Both can prescribe all POMs but pharmacists are not allowed to prescribe schedule 1 controlled drugs, once issued, a prescription is taken by the patient to a pharmacy, which dispenses the medicine. Most prescriptions in the UK are NHS prescriptions, subject to a standard charge unrelated to what is dispensed, the NHS prescription fee was increased to £8. The pharmacy charges the NHS the actual cost of the medicine, a patient can consolidate prescription charges using a prescription payment certificate, effectively capping costs at £29.10 per quarter or £104.00 per year. Outside the NHS, private prescriptions are issued by private medical practitioners, NHS supply beyond three months worth is not covered, and must be purchased privately. A patient pays the pharmacy the normal price for medicine prescribed outside the NHS, in the United States, the Federal Food, Drug, and Cosmetic Act defines what substances require a prescription in order to be dispensed by a pharmacy. The Controlled Substances Act was enacted into law by the Congress of the United States in 1970, the CSA is the federal U. S. drug law under which the manufacture, importation, possession, use and distribution of certain substances is regulated. The legislation created five schedules with varying qualifications for a substance to be included in each, the safety and effectiveness of prescription drugs in the US is regulated by the federal Prescription Drug Marketing Act of 1987. The Food and Drug Administration is charged with implementing this law, misuse or abuse of prescription drugs can lead to adverse drug events, including those due to dangerous drug interactions

10.
Pharmacokinetics
–
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism

11.
Bioavailability
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By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, its bioavailability generally decreases or may vary from patient to patient, Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. Bioavailability is defined differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food. Bioaccessibility is a related to bioavailability in the context of biodegradation. A molecule is said to be bioaccessible when is available to cross a cellular membrane from the environment. In pharmacology, bioavailability is a measurement of the rate and extent to which a drug reaches at the site of action and it is denoted by the letter f. Therefore, bioavailability for dietary supplements can be defined as the proportion of the administered substance capable of being absorbed, in both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve of the drug concentration time profile. Bioavailability is commonly a factor in the production of crops. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess and it is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be normalized, consequently, the amount absorbed is corrected by dividing the corresponding dose administered. The absolute bioavailability is the area under curve non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the route is given below. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability, although knowing the true extent of systemic absorption is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires a reference, that is. These limitations may be overcome, however, by administering a low dose of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology, the technique was first applied using stable-isotopes such as 13C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, 14C labelled drugs are administered intravenously and accelerator mass spectrometry used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug, in all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution

12.
Drug metabolism
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Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. These pathways are a form of biotransformation present in all groups of organisms. These reactions often act to detoxify poisonous compounds, the study of drug metabolism is called pharmacokinetics. The metabolism of drugs is an important aspect of pharmacology. For example, the rate of metabolism determines the duration and intensity of a drugs pharmacologic action, the enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides. Drug metabolism is divided into three phases, in phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are conjugated to polar compounds in phase II reactions. These reactions are catalysed by enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be processed, before being recognised by efflux transporters. Drug metabolism often converts lipophilic compounds into hydrophilic products that are readily excreted. The exact compounds an organism is exposed to will be unpredictable, and may differ widely over time. The solution that has evolved to address this problem is an elegant combination of physical barriers, all organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. This selective uptake means that most hydrophilic molecules cannot enter cells, in contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics and these systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general one or more charged groups. However, since these compounds are few in number, specific enzymes can recognize, the metabolism of xenobiotics is often divided into three phases, - modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells, in phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system and these enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates

13.
CYP2C19
–
Cytochrome P450 2C19 is an enzyme. This protein, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics, including many proton pump inhibitors, in humans, the CYP2C19 protein is encoded by the CYP2C19 gene. CYP2C19 has been annotated as -limonene 6-monooxygenase and -limonene 6-monooxygenase in UniProt, the gene encodes a member of the cytochrome P450 superfamily of enzymes. These proteins are monooxygenases that catalyze many reactions involved in metabolism and synthesis of cholesterol, steroids. This protein localizes to the endoplasmic reticulum and is known to many drugs. Polymorphism within this gene is associated with ability to metabolize mephenytoin, known as the poor metabolizer. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24. Along with CYP2C19, CYP2C8, CYP2C9, CYP2J2, and possibly CYP2S1 are the producers of EETs and, very likely EEQs, EDPs. Genetic polymorphism exists for CYP2C19 expression, with approximately 3–5% of Caucasian and this may reduce the efficacy of clopidogrel. The basis for this effect of clopidogrel in patients who have a gene of reduced activity may seem somewhat paradoxical. Clopidogrel is administered as a “prodrug, ” that is, a drug that is inactive when taken, in patients who have a gene of reduced activity, clopidogrel may not be metabolized to its active form and therefore not achieve pharmacological effect in the body. In patients with an abnormal CYP2C19 variant certain benzodiazepines should be avoided, such as diazepam, lorazepam, oxazepam, on the basis of their ability to metabolize -mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolizers or poor metabolizers. Eight variant alleles that predict PMs have been identified, the following is a table of selected substrates, inducers and inhibitors of CYP2C19. Where classes of agents are listed, there may be exceptions within the class, moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance of substrates. Weak being one that causes at least a 1. 25-fold but less than 2-fold increase in the plasma AUC values, cytochrome P450 oxidase PharmGKB, Annotated PGx Gene Information for CYP2C19

14.
Excretion
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Excretion is the process by which metabolic wastes and other non-useful materials are eliminated from an organism. In vertebrates this is carried out by the lungs, kidneys. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell, excretion is an essential process in all forms of life. For example, in urine is expelled through the urethra. In unicellular organisms, waste products are discharged directly through the surface of the cell, green plants produce carbon dioxide and water as respiratory products. In green plants, the carbon dioxide released during respiration gets utilized during photosynthesis, oxygen is a by product generated during photosynthesis, and exits through stomata, root cell walls, and other routes. Plants can get rid of water by transpiration and guttation. These latter processes do not need added energy, they act passively, however, during the pre-abscission phase, the metabolic levels of a leaf are high. Plants also excrete some waste substances into the soil around them, in animals, the main excretory products are carbon dioxide, ammonia, urea, uric acid, guanine and creatine. The liver and kidneys clear many substances from the blood, aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other materials as there is less water in the environment. Birds excrete their nitrogenous wastes as uric acid in the form of a paste and this is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, in insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines, the metabolic waste is then released from the body along with fecal matter. The excreted material may be called dejecta or ejecta, in pathology the word ejecta is more commonly used. UAlberta. ca, Animation of excretion Brian J Ford on leaf fall in Nature

15.
Urine
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Urine is a liquid by-product of metabolism in the bodies of many animals, including humans. It is expelled from the kidneys and flows through the ureters to the urinary bladder, cellular metabolism generates numerous by-products, many nitrogenous, that require clearance from the bloodstream. These by-products are eventually expelled from the body during urination, the method for excreting water-soluble chemicals from the body. These chemicals can be detected and analyzed by urinalysis, of the many such substances that exist, the three main nitrogenous wastes of the mammalian body are urea, uric acid, and creatinine. Animal urine forms part of the nitrogen cycle, in balanced ecosystems it fertilizes soil and plants, which in turn continue to support the animal population. Some animals use it to mark their territories, human urine and human feces are collectively referred to as human waste, as sewage, they require sewage treatment in places where population density is high. Livestock urine and feces similarly require proper management if the population density is high. Such management is part of ecological sanitation, most animals have excretory systems for elimination of soluble toxic wastes. In humans, soluble wastes are excreted primarily by the system and, to a lesser extent in terms of urea. The urinary system consists of the kidneys, ureters, urinary bladder, the system produces urine by a process of filtration, reabsorption, and tubular secretion. The kidneys extract the soluble wastes from the bloodstream, as well as water, sugars. The resulting urine contains high concentrations of urea and other substances, urine flows from the kidney through the ureter, bladder, and finally the urethra before passing from the body. Research looking at the duration of urination in a range of species found that 9 larger species urinated for 21 ±13 seconds irrespective of body size. Smaller species including rodents and bats cannot produce jets and instead urinate with a series of drops, producing too much or too little urine needs medical attention. Polyuria is a condition of excessive production of urine, oliguria when <400 mL are produced, about 91-96% of urine consists of water. Urine also contains an assortment of inorganic salts and organic compounds, including proteins, hormones, the total solids in urine are on average 59 g per person per day. Organic matter makes up between 65% and 85% of urine dry solids, with volatile solids comprising 75–85% of total solids, urea is the largest constituent of the solids, constituting more than 50% of the total. On an elemental level, human urine contains 6.87 g/L carbon,8.12 g/L nitrogen,8.25 g/L oxygen, the exact proportions vary with individuals and with factors such as diet and health

16.
Feces
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Feces or faeces are the solid or semisolid metabolic waste from an animals digestive tract, discharged through the anus or cloaca during a process called defecation. Urine and feces together are called excreta, collected feces has various uses, namely as fertilizer or soil conditioner in agriculture, as a fuel source, or for medicinal purposes. After an animal has digested eaten material, the remains of material are discharged from its body as waste. Although it is lower in energy than the food from which it is derived, feces may retain a large amount of energy and this means that of all food eaten, a significant amount of energy remains for the decomposers of ecosystems. Many organisms feed on feces, from bacteria to fungi to insects such as dung beetles, some may specialize in feces, while others may eat other foods as well. Feces serve not only as a food, but also as a supplement to the usual diet of some animals. Feces and urine, which reflect light, are important to raptors such as kestrels. Seeds also may be found in feces, animals who eat fruit are known as frugivores. An advantage for a plant in having fruit is that animals will eat the fruit and this mode of seed dispersal is highly successful, as seeds dispersed around the base of a plant are unlikely to succeed and often are subject to heavy predation. Provided the seed can withstand the pathway through the system, it is not only likely to be far away from the parent plant. This cycling of matter is known as the biogeochemical cycle, the distinctive odor of feces is due to bacterial action. Gut flora produce compounds such as indole, skatole, and thiols and these are the same compounds that are responsible for the odor of flatulence. Consumption of foods prepared with spices may result in the spices being undigested, the perceived bad odor of feces has been hypothesized to be a deterrent for humans, as consuming or touching it may result in sickness or infection. Human perception of the odor may be contrasted by an animals perception of it, for example. In humans and depending on the individual and the circumstances, defecation may occur daily, extensive hardening of the feces may cause prolonged interruption in the routine and is called constipation. Human fecal matter varies significantly in appearance, depending on diet, normally it is semisolid, with a mucus coating. The brown coloration comes from a combination of bile and bilirubin, in newborn babies, initially fecal matter is yellow-green after the meconium. This coloration comes from the presence of bile alone, throughout the life of an ordinary human, one may experience many types of feces

17.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service

18.
Guide to Pharmacology
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The IUPHAR/BPS Guide to PHARMACOLOGY is an open-access website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY is developed as a joint venture between the International Union of Basic and Clinical Pharmacology and the British Pharmacological Society and this replaces and expands upon the original 2009 IUPHAR Database. The information featured includes pharmacological data, target and gene nomenclature, overviews and commentaries on each target family are included, with links to key references. The Guide to PHARMACOLOGY was initially made available online in December 2011 with additional material released in July 2012 and its network of over 700 specialist advisors contribute expertise and data. The current PI and Grant holder of the GtoPdb project is Prof. Jamie A. Davies, the development and release of the first version of the GtoPdb in 2012 was described in an editorial published in the British Journal of Pharmacology entitled Guide to Pharmacology. org- an update. The IUPHAR-DB is no longer being developed and all the contained within this site is now available through the Guide to PHARMACOLOGY. A complete list of all the approved drugs included on the website is available via the ligand list. The Guide to PHARMACOLOGY is being expanded to include information on targets and ligands. Search features on the website include quick and advanced search options, other features include Hot topic news items and a recent receptor-ligand pairing list. A hard copy summary of the database is published as The Concise Guide to Pharmacology 2015/2016 as a series of papers as a bi-annual supplement to the British Journal of Pharmacology. The Guide to PHARMACOLOGY includes links to other relevant resources via target, many of these resources maintain reciprocal links with the relevant Guide to PHARMACOLOGY pages. As of November 2015 the Wellcome Trust is supporting a new project to develop the Guide to Immumopharmacology, the latter continues to be supported by the British Pharmacological Society

19.
DrugBank
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The DrugBank database is a comprehensive, freely accessible, online database containing information on drugs and drug targets. As both a bioinformatics and a resource, DrugBank combines detailed drug data with comprehensive drug target information. Because of its scope, comprehensive referencing and unusually detailed data descriptions. As a result, links to DrugBank are maintained for nearly all drugs listed in Wikipedia, DrugBank is widely used by the drug industry, medicinal chemists, pharmacists, physicians, students and the general public. Its extensive drug and drug-target data has enabled the discovery and repurposing of a number of existing drugs to treat rare, the latest release of the database contains 8227 drug entries including 2003 FDA-approved small molecule drugs,221 FDA-approved biotech drugs,93 nutraceuticals and over 6000 experimental drugs. Additionally,4270 non-redundant protein sequences are linked to these drug entries, each DrugCard entry contains more than 200 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. Four additional databases, HMDB, T3DB, SMPDB and FooDB are also part of a suite of metabolomic/cheminformatic databases. The first version of DrugBank was released in 2006 and this early release contained relatively modest information about 841 FDA-approved small molecule drugs and 113 biotech drugs. It also included information on 2133 drug targets, the second version of DrugBank was released in 2009. This greatly expanded and improved version of the database included 1344 approved small molecule drugs and 123 biotech drugs as well as 3037 unique drug targets. Version 2.0 also included, for the first time, withdrawn drugs and illicit drugs, version 3.0 was released in 2011. This version contained 1424 approved small molecule drugs and 132 biotech drugs as well as >4000 unique drug targets, version 3.0 also included drug transporter data, drug pathway data, drug pricing, patent and manufacturing data as well as data on >5000 experimental drugs. Version 4.0 was released in 2014 and this version included 1558 FDA-approved small molecule drugs,155 biotech drugs and 4200 unique drug targets. Version 4.0 also incorporated information on drug metabolites, drug taxonomy, drug spectra, drug binding constants. Table 1 provides a complete statistical summary of the history of DrugBank’s development. All data in DrugBank is non-proprietary or is derived from a non-proprietary source and it is freely accessible and available to anyone. In addition, nearly every item is fully traceable and explicitly referenced to the original source. DrugBank data is available through a web interface and downloads

20.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses

21.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets

22.
Chemical formula
–
These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH

23.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D

24.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES

25.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure

26.
Tricyclic antidepressant
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Tricyclic antidepressants are chemical compounds used primarily as antidepressants. TCAs were first discovered in the early 1950s and marketed later in the decade and they are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants, which contain four rings of atoms, are a related group of antidepressant compounds. Adverse effects have been found to be of a level between TCAs and SSRIs. The TCAs were developed amid the explosive birth of psychopharmacology in the early 1950s, the story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulencs chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952, the first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to other derivatives of chlorpromazine. The first TCA reported for the treatment of depression was imipramine and it was not originally targeted for the treatment of depression. The drugs tendency to induce manic effects was later described as in some patients, the paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957, some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ciba-Geigy and eventually Novartis, dibenzazepine derivatives are described in U. S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline, merck introduced the second member of the TCA family, amitriptyline, in 1961. This compound has a different three-ring structure than imipramine, the TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder, dysthymia, and treatment-resistant variants. For many years the TCAs were the first choice for treatment of clinical depression. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes, nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants. They are not considered addictive and are preferable to the monoamine oxidase inhibitors. ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the cortex of the brain. Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, the TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia

Medical Officer Alexander Fleming, M. D., examines a portion of a 240-volume new drug application around the late 1980s. Applications grew considerably after the efficacy mandate under the 1962 Drug Amendments.

Graph that demonstrates the Michaelis–Menten kinetics model for the relationship between an enzyme and a substrate: one of the parameters studies in pharmacokinetics, where the substrate is a pharmaceutical drug.

Different forms of tablets, which will have different pharmacokinetic behaviours after their administration.

The time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours. Note that the AUC in steady state equals AUC∞ after the first dose.

A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal …

Hyperforin, the primary active constituent responsible for the therapeutic benefits of extracts of the herb Hypericum perforatum (St. John's Wort), which is used as an antidepressant.

Escitalopram, a selective serotonin reuptake inhibitor (SSRI) used as an antidepressant.

Tiagabine, a selective GABA reuptake inhibitor used as an anticonvulsant in the treatment of epilepsy and seizures.

Reserpine, a vesicular reuptake inhibitor that was used in the past to deplete serotonin, norepinephrine, and dopamine stores as an antipsychotic and antihypertensive. It was notorious for causing anxiety and depression, and as a result, was replaced by newer, more modern drugs instead.